We have previously shown that the density of capillary supply in skeletal muscle of man correlates with insulin resistance. We postulated that since the unfenestrated capillaries of muscle are relatively impermeable to insulin that the increased insulin resistance in those with low capillary density might be due to altered kinetics of insulin penetration to its sites of action in muscle. We have published a method of directly collecting lymph from a peripheral lymphatic vessel in sufficient amounts to measure insulin, and glucose during changes in arterial insulin. Insulin concentrations in limb lymph are much lower than in plasma and in contrast to plasma are highly correlated with glucose uptake in each individual. However, compared to obese insulin resistant subjects, the slope of the glucose uptake/insulin relationship is much steeper in lean subjects. Hence, interstitial insulin concentrations determine insulin action but individual variations in insulin resistance are determined more distally in the pathway leading to insulin mediated glucose uptake.